The demand for enantiomerically pure compounds has grown rapidly in recent years. One important use for such chiral, non-racemic compounds is as intermediates for synthesis in the pharmaceutical industry. For instance, it has become increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. These advantages include the fewer side effects and greater potency often associated with enantiomerically pure compounds.
Traditional methods of organic synthesis were often optimized for the production of racemic materials. The production of enantiomerically pure material has historically been achieved in one of two ways: use of enantiomerically pure starting materials derived from natural sources (the so-called “chiral pool”); and the resolution of racemic mixtures by classical techniques. Each of these methods has serious drawbacks, however. The chiral pool is limited to compounds found in nature, so only certain structures and configurations are readily available. Resolution of racemates, which requires the use of resolving agents, may be inconvenient and time-consuming.
Enantiomerically pure materials may be obtained by asymmetric conjugate addition of a nucleophile to an electron-poor alkene. The asymmetric conjugate addition is one of the most powerful bond-forming reactions to construct enantioenriched, highly functional carbon skeletons for the total synthesis of natural and biologically active compounds. For reviews see: (a) B. E. Rossiter, N. M. Swingle, Chem. Rev. 1992, 771-806; (b) J. Leonard, E. Diez-Barra, S. Merino, Eur. J. Org. Chem. 1998, 2051-2061; (c) K. Tomioka, Y Nagaoka, Comprehensive Asymmetric Catalysis (Eds.: E. N. Jacobsen, A Pfaltz, H. Yamamoto), Springer, Berlin, 1999, vol. 3, p. 1105-1120; (d) M. Yamaguci, Comprehensive Asymmetric Catalysis (Eds.: E. N. Jacobsen, A Pfaltz, H. Yamamoto), Springer, Berlin, 1999, vol. 3, p. 1121-1139; (e) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033-8061; (f) N. Krause, A. Hoffmann-Roder Synthesis 2001, 171-196. For general reviews on conjugate additions see: (g) P Perlmutter, Conjugate Addition Reactions in Organic Synthesis (Eds.: J. E. Baldwin, P D. Magnus), Pergamon Press, Oxford, 1992; (h) M. E. Jung, Comprehensive Organic Synthesis (Ed.: B. M. Trost), Pergamon Press, Oxford, 1991, vol. 4, pp. 1-67. Its strategic importance is evident by considering that a Michael addition can represent the initiating step of more complex inter- and intramolecular tandem processes. For reviews see: (a) L. F Tietze, Chem. Rev. 1996, 96, 115-136; (b) R. A. Brunce, Tetrahedron 1995, 48, 13103-13159; (c) L. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137-170; Angew Chem. Int. Ed Engl. 1993, 32, 131-163; (d) G. H. Posner, Chem. Rev. 1986, 86, 831-844.
Among the Michael acceptors, nitroalkenes are very attractive, because the nitro group is the most electron-withdrawing group known. N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH, New York, 2001; D. Seebach, E. W. Colvin, F Lehr, T Weller, Chimia 1979, 33, 1-18. Often described as a “synthetic chameleon,” the nitro group can serve as masked functionality to be further transformed after the addition has taken place. G. Calderari, D. Seebach, Helv. Chim. Acta 1995, 68, 1592-1604. The Nef reaction, the nucleophilic displacement, the reduction to amino group, the Myer reaction, and the conversion into a nitrile oxide are only examples of the transformations that nitro groups can undergo. H. W. Pinnick, Org. React. 1990, 38, 655-792; J. U. Nef, Justus Liebigs Ann. Chem. 1894, 280, 263-291; R. Tamura, A. Kamimura, N. Ono, Synthesis 1991, 423-434; R. C. Larock, Comprehensive Organic Transformations, VCH, New York, 1989, pp. 411-415; A. K. Beck, D. Seebach, Chem. Ber. 1991, 124, 2897-2911; R. E. Maeri, J. Heinzer, D. Seebach, Liebigs Ann. 1995, 1193-1215; M. A. Poupart, G. Fazal, S. Goulet, L. T Mar, J. Org. Chem. 1999, 64, 1356-1361; A. G. M. Barrett, C. D. Spilling, Tetrahedron Lett. 1988, 29, 5733-5734; D. H. Loyd, D. E. Nichols, J. Org. Chem. 1986, 51, 4294-4298; V. Meyer, C. Wurster, Ber. Dtsch. Chem. Ges. 1873, 6, 1168-1172; M. J. Kamlet, L. A. Kaplan, J. C. Dacons, J Org. Chem. 1961, 26, 4371-4375; T. Mukayama, T Hoshino, J. Am. Chem. Soc. 1960, 82, 5339-5342. A number of catalytic synthetic methods have been developed in recent years, making use of nitroalkenes even more attractive. A. G. M. Barret, G. G. Graboski, Chem. Rev. 1986, 86, 751-762; R. Ballini, R. Castagnani, M. Petrini, J. Org. Chem. 1992, 57, 2160-2162; G. Rosini, R. Ballini, M. Petrini, P Sorrenti, Synthesis 1985, 515-517.
Conjugate additions of carbon nucleophiles to alkenyl sulfones in parallel to those to nitroalkenes constitute a class of synthetically valuable C—C bond forming reactions. Accordingly, considerable efforts have been devoted to the development of asymmetric conjugate additions to alkenyl sulfones. Although significant advancements have been made in the use of chiral auxiliary strategy, the realization of a highly enantioselective catalytic conjugate additions with alkenyl sulfones remains elusive. For reviews of enantioselective conjugate additions, see (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033-8061; (b) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171-196; (c) M. Yamaguchi in Comprehensive Asymmetric Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg, 2003, Suppl. 1, Supplement to chap. 31.2, p. 151. (a) Pinheiro, S.; Guingant, A.; Desmaëile, D.; d'Angelo, J. Tetrahedron: Asymmetry 1992, 3, 1003; (b) d'Angelo, J.; Revial, G. Tetrahedron: Asymmetry 1991, 2, 199. Lin, Y.; Ali, B. E.; Alper, H. J. Am. Chem. Soc. 2001, 123, 7719. For a conjugate addition of chiral 1-aminopyrrolidine to alkenyl sulfones see: Enders, D.; Müller, S. F.; Raabe, G.; Runsink, J. Eur. J. Org. Chem. 2000, 879. (a) Reddick, J. J.; Cheng, J.; Roush, W. R. Org. Lett. 2003, 5, 1967; (b) Sanki, A. K.; Suresh, C. G.; Falgune, U. D.; Pathak, T. Org. Lett. 2003, 5, 1285; (c) Ravindran, B.; Sakthivel, K.; Suresh, C. G.; Pathak, T. J. Org. Chem. 2000, 65, 2637; (d) Farthing, C.; Marsden, S. P. Tetrahedron Lett. 2000, 41, 4235-4238; (e) Hirama, M.; Hioki, H.; Itô, S.; Kabuto, C. Tetrahedron Lett. 1988, 29, 3121. For intramolecular Michael addition to alkenyl sulfones see: Carretero, J. C.; Arráyas, R. G. J. Org. Chem. 1998, 63, 2993; for a Rh-catalyzed enantioselective conjugate addition of organoboronic acids to trans-β-substituted vinyl sulfones see: Mauleón, P.; Carretero, J. C. Org. Lett. 2004, 6, 3195.
Additionally, the conjugate addition of carbon nucleophiles to alkenyl ketones provides a powerful strategy for the creation of all-carbon quaternary stereocenters, due to the accessibility of a wide range of both the Michael donors and acceptors and the proven wide utility of the 1,4-adducts. Remarkably, in spite of numerous great strides made since then in catalytic asymmetric synthesis, this task remains a daunting challenge of undiminished synthetic significance. Wynberg, H.; Helder, R. Tetrahedron Letters 1975, 46, 4057-4060. Sawamura, M.; Hamashima, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 8295-8296. Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M. Tetrahedron Letters 1996, 37, 5561-5564. Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240-11241. Bella, M.; Jørgensen, A. J. Am. Chem. Soc. 2004, 126, 5672-5673. For chiral (salen)A1 complex-catalyzed conjugate addition of α-phenyl α-cyanoacetate to an acyclic α,β-unsaturated ketones, see Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313-1317. For a special issue focusing on asymmetric catalysis, see: Proc. Natl. Acad. Sci. USA 2004, 101, 5347-5850. (b) For a thematic issue for Enantioselective Catalysis see: (Eds: Bolm, C.; Gladysz, J.) Chem. Rev. 2003, 103, 2761-3400. (c) Comprehensive Asymmetric Catalysis, E. N. Jacobsen, A. Pfaltz, H. Yamamoto Eds, Springer-Verlag, Berlin, 1999, Vol. 1-3. An enantioselective catalytic conjugate addition of α-substituted ketoesters to vinyl ketones was reported by Shibasaki and coworkers in 1994. Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M. Tetrahedron Letters 1996, 37, 5561-5564. With a bifunctional chiral La—Na-BINOL complex, the addition of cyclic and acyclic α-substituted ketoesters to methyl vinyl ketone (MVK) proceeded in 62-91% ee. More recently, Sodeoka and coworkers reported a Pd-BINAP complex that afforded 86-93% ee for the conjugate addition of α-substituted ketoesters to methyl and ethyl vinyl ketones. Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240-11241. These chiral metal complex-mediated reactions, while demonstrating substantial scopes with respect to ketoester donors, afforded greater than 90% ee only with MVK as the Michael acceptor. Moreover, performed at −50 to −20° C., a catalyst loading of 5-10 mol % is required for the reaction to reach completion in 15 to 72 hours. Although representing remarkable progresses, these results underscore both the urgency and challenge for the development of an operationally simple, efficient and rapid enantioselective catalytic conjugate addition of broad substrate scopes for alkenyl ketones.
The present invention relates to the catalytic asymmetric synthesis of chiral compounds from prochiral substrates, such as nitroalkenes, alkenyl sulfones and alkenyl ketones.
Catalytic asymmetric synthesis is providing chemists with new and powerful tools for the efficient synthesis of complex molecules. While many of the catalytic systems are metal-based and rely on chiral Lewis acid and organometallic redox-based catalysis, increasing numbers of asymmetric reactions are catalyzed by chiral nucleophiles, building on the vast assortment of situations in nature in which nucleophiles play pivotal roles. For leading references, see: (a) In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999; (b) In Asymmetric Catalysis in Organic Synthesis, Noyori, R., Ed.; Wiley: New York, 1994; (c) In Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; VCH: New York, 2000; (d) Acc. Chem. Res. 2000, 33, 323. (e) Groger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529; (f) Pierre, J.-L. Chem. Soc. Rev. 2000, 29, 251-257. (g) Roberts, B. P. Chem Soc. Rev. 1999, 28, 25. Chiral amines play a central role in this expanding area of asymmetric catalysis. Although chiral amines have been utilized extensively as chiral ligands, they have also shown great promise in catalyzing a broad range of asymmetric transformations, yielding optically enriched products in high selectivity and yield that may not be accessible through alternative asymmetric technology. Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis; Wiley & Sons: New York, 1995.
Historically, the cinchona alkaloids were the first chiral amines to be used in asymmetric catalysis, most notably in the pioneering work of Pracejus from the 1960's on disubstituted ketene alcoholysis. Cinchona alkaloids also possess a rich and colorful history that is rooted in natural products and pharmaceutical chemistry. Turner, R. B.; Woodward, R. B. In In the Alkaloids; Manske, R. H. F.; Holmes, H. L., Eds.; Academic Press: New York, 1953; Vol. 3, p 24; Verpoorte, R.; Schripsema, J.; Van der Leer, T. In In the Alkaloids. Chemistry and Pharmacology, Brossi, A., Ed.; Academic Press: New York, 1988; Vol. 34; Michael, J. P. In The Quinoline Alkaloids, In Rodd's Chemistry of Carbon Compounds, 2nd ed.; Sainsbury, M., Ed.; Elsevier: Amsterdam, 1998; 2nd suppl., part F and G, vol 4; 432. They are isolated en masse by extracting the bark of the cinchona tree, which is native to tropical regions. Outside of organic chemistry, the cinchona alkaloids have found wide use as food flavorings (for example as the bitter principle of tonic water) and in the treatment of malaria. Fletcher, D. C. J. Am. Med. Assoc. 1976, 236, 305; Mturi, N.; Musumba, C. O.; Wamula, B. M.; Ogutu, B. R.; Newton, C. R. J. C. CNS Drugs 2003, 17, 153. Additionally, their roles as ligands, chromatographic selectors, and NMR discriminating agents have been examined extensively over the past thirty years. Several reviews have been published on the catalytic chemistry of cinchona alkaloids over the past four decades. Pracejus, H. Forschr. Chem. Forsch. 1967, 8, 493; Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions; Prentice Hall: Englewood Cliffs, 1971; Wynberg, H. Top. Stereochem. 1986, 16, 87; Kacprzak, K.; Gawronski, J. Synthesis 2001, 7, 961.
These reactions appear to be broadly applicable to both research and industrial scale asymmetric synthesis of a wide variety of important chiral building blocks, such as hemi-esters, α-amino acids and α-hydroxy acids. Commercially available modified dimeric cinchona alkaloids (DHQD)2AQN, (DHQ)2AQN (see FIG. 1), have been identified recently by Deng and coworkers as enantioselective and recyclable catalysts for enantioselective alcoholyses of cyclic anhydrides. However, commercially available (DHQD)2AQN is expensive. For example, the commercial price (Aldrich Chemical Company) for a mole of (DHQD)2AQN is more than $100,000.00. Furthermore, the dimeric catalyst is not available in large quantity (e.g., in kilogram quantity). Therefore, stereoselective reactions using dimeric catalysts are not practical on a relatively large scale (>0.1 mol). Consequently, the development of a new generation of monomeric catalysts that is comparably effective to (DHQD)2AQN, but substantially less costly to produce, is of significant practical value.
Chiral metal and organic catalysts that possess both an acidic and a basic/nucleophilic structural moiety constitute an increasingly powerful platform for the development of asymmetric catalysis. The design and development of such bifunctional chiral catalysts that are efficient yet easily accessible continues to be a major challenge. Wynberg and coworkers demonstrated that natural cinchona alkaloids, via their C9-OH and amine groups, served as bifunctional chiral organic catalysts by activating the nucleophile and electrophile, respectively, for enantioselective reactions. Wynberg, H., Hiemstra, H., J. Am. Chem. Soc., 1981, 103, 417. However, the enantioselectivity of various reactions catalyzed by natural cinchona alkaloids as chiral organic catalysts was usually modest. Hatakeyama and coworkers recently reported a rigid modified cinchona alkaloid that is readily accessible from quinidine. Hatakeyama, S. et al., J. Am. Chem. Soc., 1999, 121, 10219; Hatakeyama, S., Organic Lett., 2003, 5, 3103. The catalyst was found to be efficient for an enantioselective Morita-Baylis-Hillman (MBH) reaction. Both the C6′-OH and the amine groups are believed to be involved in the stabilization of the transition state of the enantioselective MBH reaction.
Remarkably, readily accessible bifunctional organic catalysts that can be derived from either quinidine or quinine have been developed, and their successful use in asymmetric carbon-carbon-bond-forming reactions has been demonstrated.